Clinical Data CD16+/+/mbIL-15+/+ Double Knock-in (DKI) ApproachIPSC’s were edited at the GAPDH locus using the Company’s proprietary SLEEK (SeLection by Essential-gene Exon Knock-in) technology and engineered AsCas12a nuclease to knock-in both CD16 and membrane-bound IL-15 (mbIL-15). CD16+/+/mbIL-15+/+ edits were designed to increase antibody-dependent cellular cytotoxicity (ADCC) when combined with tumor-targeting antibodies and prolong iNK cell persistence.
DKI iNK cells, as monotherapy or in combination with trastuzumab, showed significantly enhanced tumor killing compared with wild type (WT) iNKs in an in vitro 3D SKOV-3 ovarian tumor spheroid assay. Evaluation in an in vivo mouse SKOV-3 cancer model confirmed that DKI iNKs combined with trastuzumab exerted greater anti-tumor activity compared to WT iNKs with trastuzumab, or trastuzumab alone. A single dose of DKI iNKs combined with three doses of trastuzumab induced complete tumor clearance in 50 percent of mice (n=4/8). Importantly, DKI iNKs were detected in the peritoneum of the treated mice for greater than three (3) months, demonstrating that the mbIL-15 maintained iNK survival for a prolonged period in the absence of exogenous cytokine support.
CISH-/-/TGFβR2-/- Double Knock-out (DKO) ApproachIn a separate study, iPSCs were edited with Editas-engineered AsCas12a to knock out both the CISH and TGFβ-receptor 2 (TGFβR2) genes. CISH-/-/TGFβR2-/- edits were designed to improve iNK cell effector function and provide resistance to TGFβ-mediated NK suppression in the tumor microenvironment. DKO iNKs induced enhanced tumor killing against in vitro 3D SKOV-3 ovarian tumor spheroids compared to WT iNKs. Following stimulation, DKO iNKs produced elevated levels of inflammatory cytokines, including IFN-γ and TNF-α. The DKO iNK cells also induced significant reduction in tumor burden compared with WT iNK treatment when tested in vivo in a SKOV-3 ovarian cancer mouse model.
“In this promising research, we demonstrate the use of our proprietary engineered AsCas12a nuclease and SLEEK technology with its high efficiency, multi-transgene editing capability to enable the efficient development and evaluation of multiple iNK therapeutic approaches. Using selective, double knock-in and double knock-out strategies, we have developed allogenic iNK cell lines with substantially enhanced in vitro and in vivo anti-tumor activity, reducing or eliminating tumors in tumor-bearing mice. The potency of both modified iNK cell therapeutic approaches supports their continued development as novel cell-based medicines for the treatment of cancer,” said Mark S. Shearman, Ph.D., Executive Vice President and Chief Scientific Officer, Editas Medicine. “We believe that NK cells are attractive candidates for off-the-shelf immunotherapy medicines given their high tumor killing capacity and their low propensity for graft-versus-host disease. Furthermore, our approach builds in safeguards by screening and selecting iPSC clones that are fully characterized, eliminating those with chromosomal abnormalities and ensuring a pure final population of cells. These data reinforce our view of the potential for our gene editing platform to optimize NK cell function, providing a promising approach to treat a wide range of solid tumors.”